Fatty acid binding proteins, FABPs, have been identified as central regulators of both metabolic and inflammatory pathways. FABPs act as intracellular receptors for a variety of hydrophobic compounds, enabling their diffusion within the cytoplasmic compartment. We have shown that adipocyte FABP (A-FABP) and epithelial FABP (E-FABP) regulate macrophage cholesterol trafficking and inflammatory function, in part via regulation of the activity of the peroxisome proliferator-activated receptor ( (PPAR(). Macrophages and dendritic cells (DC) from FABP- deficient mice are defective in expression of proinflammatory cytokines and are inefficient in the promotion of proinflammatory T cells responses during antigen presentation. FABP-deficient mice are protected from development of experimental autoimmune encephalomyelitis (EAE). Overall, the results of our research suggest that FABPs regulate a molecular switch between metabolic and inflammatory pathways in macrophages and DC and, as a consequence, regulate both innate and adaptive immune responses. We will continue our studies of these proteins through the pursuit of the following specific aims: Specific Aim 1 is to identify the molecular mechanism(s) by which FABPs affect inflammatory cytokine gene expression in macrophages and DC. We have found that FABP- deficiency is accompanied by elevated activity of AMP-activated protein kinase (AMPK) and that AMPK is a negative regulator of macrophage inflammatory function. Experiments will be performed to determine the link between FABPs, AMPK, and PPAR(, testing the hypothesis that FABP regulation of energy stores regulates AMPK activity, which in turn modulates inflammatory activity. Specific Aim 2 is to further delineate the impact of FABP-deficiency on autoimmune disease using EAE as a model. This aim will include an evaluation of the specific contributions of T cell priming, and of the tissue environment, towards the protection from EAE displayed by FABP-deficient mice. Specific Aim 3 is to test the hypothesis that the expression of FABPs links dietary fat intake with exacerbated inflammatory disease. We will evaluate the effects of fat intake on FABP expression in leukocyte population and the association of diet-induced FABP expression with inflammatory responsiveness. FABPs are considered potential therapeutic targets for a number of diseases. This proposal is designed to gain a more complete understanding of how these proteins regulate immune and inflammatory responses.